In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On June 13, 2013, denosumab (Xgeva) was approved for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.1,2 Denosumab is already indicated for prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.
Approval was based on demonstration of durable objective responses in two multicenter open-label trials in a total of 304 adults and skeletally mature adolescents (n = 10) with histologically confirmed, measurable giant cell tumor of bone. The tumors were recurrent, unresectable, or located where planned surgery was likely to result in severe morbidity.
Patients in these trials received subcutaneous denosumab at 120 mg every 4 weeks with additional doses on days 8 and 15 of the first month. Patients receiving concurrent bisphosphonate therapy were excluded from both trials and patients with history of osteonecrosis of the jaw or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, unhealed dental/oral surgery, or any planned invasive dental procedure were excluded from the larger (N = 282) of the two trials. During the trials, serum chemistries including calcium and phosphorus were monitored every 4 weeks, and calcium and vitamin D supplementation was recommended but not required.
Radiographic assessments at baseline and following denosumab treatment were available for 187 (61%) patients. A retrospective assessment by an independent review committee found objective response (all partial responses) in 47 (25%) of the 187 patients. Median time to response was 3 months. The median duration of follow-up was 20 months (range 2–44 months) in responders, with 51% (n = 24) having responses lasting at least 8 months, and three patients experiencing disease progression following response.
How It Works
The human monoclonal antibody denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, which are the cells responsible for bone resorption. Increased osteoclast activity stimulated by RANKL is a mediator of bone pathology in solid tumors with osseous metastases. Giant cell tumors of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptors; signaling through the RANK receptor contributes to osteolysis and tumor growth. Denosumab prevents RANKL from activating RANK receptors on the surface of osteoclasts, osteoclast precursors, and osteoclast-like giant cells.
How It Is Given
The recommended dose of denosumab in patients with giant cell tumor of bone is 120 mg every 4 weeks given subcutaneously in the upper arm, upper thigh, or abdomen, with additional 120 mg doses on days 8 and 15 of the first month of therapy. Calcium and vitamin D should be taken as necessary to treat or prevent hypocalcemia.
There is no evidence that anticancer treatments affect denosumab exposure or pharmacodynamics. Serum denosumab concentrations at 1 and 3 months and reductions in bone turnover markers at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy or hormone therapy.
Safety was evaluated in 304 patients, of whom 145 were treated for at least 1 year. The median number of doses given was 14. Patients had a median age of 33 years, 58% were women, and 80% were white. The adverse event profile was similar to that in patients with bone metastases from solid tumors.
The most common adverse events (≥ 10% incidence) were arthralgia, headache, nausea, back pain, fatigue, and extremity pain. Moderate hypocalcemia occurred in 2.6% of patients and severe hypophosphatemia in 9.5%. Osteonecrosis of the jaw was confirmed in four patients (1.3%), with a median time to onset of 16 months (range, 13–20 months). The most common adverse events resulting in discontinuation of treatment were osteonecrosis of the jaw (0.7%) and tooth abscess or tooth infection (0.7%). The adverse event profile appeared similar in skeletally mature adolescents and adults.
Denosumab carries warnings/precautions for hypocalcemia (including fatalities), osteonecrosis of the jaw, and embryo-fetal toxicity. Patients should have hypocalcemia corrected before starting denosumab treatment, and calcium levels should be monitored regularly, with all patients receiving adequate calcium and vitamin D supplementation. Patients with creatinine clearance less than 30 mL/min or on dialysis are at increased risk for hypocalcemia.
Patients should receive an oral exam prior to starting treatment and should be monitored for symptoms of osteonecrosis of the jaw. Dental procedures should be avoided during treatment.
Women of reproductive potential should be advised of risk to the fetus and to use effective contraception. Nursing mothers should discontinue nursing or denosumab based on consideration of importance of denosumab treatment to the mother. ■
1. U.S. Food and Drug Administration: Denosumab. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm356667.htm. Accessed July 3, 2013.
2. XGEVA® (denosumab) injection prescribing information, Amgen Inc, June 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf. Accessed July 3, 2013.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).